LIGHT is a recently discovered TNF super family cytokine expressed by activated T cells, dendritic cells (DC) and monocytes. It binds to two receptors: HVEM and the lymphotoxin (LT) b receptor. LIGHT has been reported to co-stimulate T cells during priming and to promote Th1 cytokine synthesis. Consistent with this, we and other groups have reported that constitutive LIGHT expression by T cells of transgenic mice leads to inflammation of the intestine and other organs. By contrast, using a colitis model that relies upon CD4+ T cell transfer to immune deficient recipients, we have found that the normal expression of LIGHT by APC slows disease progression. We therefore propose that LIGHT can have opposing effects: promoting inflammation when over expressed in T cells and preventing it when expressed normally in APC. The experiments in this proposal will use the T cell transfer model of colitis induction to determine how LIGHT expression by APC modulates colitis pathogenesis, analyzing the cell types affected, the receptor(s) LIGHT interacts with to modulate disease, and the cell types expressing these receptors. In vitro experiments will be carried out to identify possible mechanisms for the in vivo effects. We also will determine how constitutive expression of LIGHT by T cells leads to accelerated disease. The experiments in this proposal will provide a thorough analysis of the contrasting roles of LIGHT expression in colitis pathogenesis in mice, which could provide the basis for understanding its role in other autoimmune conditions. Blockade of LT/LIGHT signals is currently being explored as a treatment for human autoimmune diseases. The experimental results derived from the proposed experiments could provide important insights into the mechanisms for the beneficial and potentially harmful effects of such a blockade.